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10/23/2013
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Pediatric ALLPediatric ALL--Update on TreatmentUpdate on Treatment
Susan R. Rheingold, M.D.Susan R. Rheingold, M.D.
October 23, 2013October 23, 2013
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Types of Childhood CancerTypes of Childhood Cancer
CNS Tumors
20%
Retinobl.
3%
Neurobl.
8%
Wilms
7%
Liver
2%
Sarcomas
7%
Bone
5%
Lymphomas
12% Other
6%
LEUKEMIA 30% LEUKEMIA 30%
(25% ALL)(25% ALL)
~2,500 children/yr ~2,500 children/yr diagnosed with diagnosed with ALL and rising ALL and rising
ALL Incidence and EFSALL Incidence and EFS
Smith MA et al. JCO May 2010
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Clinical Clinical Presentation Presentation
of of ALLALL
Diagnostic ProceduresDiagnostic Procedures
�� BM Aspirate & BiopsyBM Aspirate & Biopsy
–– MorphologyMorphology
–– ImmunohistochemistryImmunohistochemistry / Flow / Flow CytometryCytometry
–– CytogeneticsCytogenetics
–– Microarray (SNP)Microarray (SNP)
–– Biology studiesBiology studies
�� Spinal Tap Spinal Tap –– CNS 1 (no leukemia) CNS 1 (no leukemia)
–– CNS 2 (minimal leukemia)CNS 2 (minimal leukemia)
–– CNS 3 (lots of leukemia)CNS 3 (lots of leukemia)
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Under the microscopeUnder the microscope
NCI/Rome Risk NCI/Rome Risk Classification for ALLClassification for ALL
Age WBC < 50,000/µl WBC ≥ 50,000/µl
< 1 year Infants (3%)
1-10 years Standard risk (58%)
≥≥≥≥ 10 years High risk (39%)
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Immunophenotyping / Flow
Childhood ALL Cytogenetics
Good
Prognosis
12%
88%
Pui, NEJM 2004
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Microarray/SNPMicroarray/SNP
Why mapping the human genome was worth every penny: Why mapping the human genome was worth every penny:
GenomeGenome--Wide Analyses to Discover Cancer PathwaysWide Analyses to Discover Cancer Pathways
DiagnosisRelapse
Gene Expression Copy Number
SequencingMethylation
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Borowitz, M. J. et al. Blood 2008;111:5477-5485
MRD: A stronger predictor of MRD: A stronger predictor of outcome in ALLoutcome in ALL
Day 29
MRD
POG 9900 seriesBorowitz, M. J. et al.
Blood 2008;111:5477-5485
More Predictive With Time
St. Judes
Coustan-Smith, et. al.
Blood 2000
END CONSOLIDATION
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Borowitz, M. J. et al. Blood 2008;111:5477-5485
MRD Trumps Cytogenetics
MRD in B vs T-ALL
Willemse. et al. Blood 2008 (BFM)
COG ALL treatment allocation COG ALL treatment allocation --20132013
Age WBC < 50,000/µl WBC ≥ 50,000/µl
< 1 year Infants (3%)
1-9.99 yrsStandard Risk (52%)
High Risk (25%)
Very High Risk (20%)
BB--cellcell
TT--cellcell
LOW
INTER
HIGH
Ph+ chemo/TKI
10-13 years
>13 years
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B-ALL Post-Induction Risk Groups
Risk Group
Low Average High Very High
5-yr EFS >95% 90-95% 88-90% <80%
NCI Risk
GroupSR SR SR SR SR
HR
<13yoSR HR
Favorable
geneticsYes Yes No Yes No - No -
MRD d8
(PB)<0.01 >0.01 <1 - >1 - - -
MRD d29
(BM)<0.01 <0.01 <0.01 >0.01 <0.01 <0.01 >0.01 >0.01
Therapy and Biology
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Years From Study Entry
0
20
40
60
80
100
0 2 4 6 8 10 12
1996-2000(n=3421)
1989-1995(n=5121)
1983-1988(n=3711)
1978-1983(n=2984)
1975-1977(n=1313)
1972-1975(n=936)
1970-1972(n=499)
1968-1970(n=402)
Why do Clinical Trials?Why do Clinical Trials?(COG ALL trial outcome)(COG ALL trial outcome)
How far have we come?How far have we come?COG COG 5yr EFS5yr EFS
Hunger SP et al. JCO May 2012
90%88%
84%
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Why aren’t the 15Why aren’t the 15--21 year olds 21 year olds doing better?doing better?
Best Therapy for Adolescents Best Therapy for Adolescents (15(15--21 years)21 years)
Wood, W. Blood 2011
Last COG Trial
> 16 years – 79% 5yr EFS
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What do Clinical Trials What do Clinical Trials for ALL Ask?for ALL Ask?
1) Reduction in Therapy Questions: 1) Reduction in Therapy Questions: Decrease toxicity and late effectsDecrease toxicity and late effects
2) “Re2) “Re--arranging the Deck Chairs”:arranging the Deck Chairs”:
Varying the drug, dose, orderVarying the drug, dose, order
3) Introducing New Agents: 3) Introducing New Agents:
Higher cure rates? Higher cure rates?
Toxicity / TolerabilityToxicity / Tolerability
Reduction in TherapyReduction in Therapy
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Changing Drug or DoseChanging Drug or Dose
What is the best way to give What is the best way to give MethotrexateMethotrexate??
HD MTX
IV MTX
AALL0232
AALL0232
Dex x 14 days for ≤ 10 years
Pred x 28 days for > 10 years
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Adding New AgentsAdding New Agents
�� Newer chemotherapy agentsNewer chemotherapy agents
–– ClofarabineClofarabine
–– NelarabineNelarabine -- T cell targeted drugT cell targeted drug
�� Targeted agentsTargeted agents
–– ImatinibImatinib//DasatinibDasatinib
–– LestaurtinibLestaurtinib for MLLfor MLL
�� ImmunotherapyImmunotherapy
–– Monoclonal AntibodiesMonoclonal Antibodies
–– Engineered TEngineered T--cellscells
VHR ALL VHR ALL -- SchemaSchemaInduction
Control Arm
Consolidation (Day 1-28)
Consolidation
(Day 29-57)
MBFM
Evaluation (MRD Flow)
Exp Arm 1 Exp Arm 2
Consolidation
(Day 29-57)
CPM/ETOP
Consolidation
(Day 29-57)
CLOF/CPM/ETOP
Interim Maintenance I
HD MTX x 4
Delayed Intensification (Day 1-28)
MBFM
Delayed Intensification(Day 29-57)MBFM CPM/ETOP
Delayed Intensification (Day 29-57)CPM/ETOP CLOF/CPM/ETO
P
Delayed Intensification (Day 29-57)
CLOF/CPM/ETOP
Interim Maintenance II Outpt MTX
Hypodiploidy,
Induction failure
Patients will have
the option of
receiving SCT
Maintenance
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AALL0434 Induction
AALL0434-LOW AALL0434-INTER/HIGH
- NCI SR or HR
– RER or SER
- MRD <1% day 29
Day 15 BM Response, DAY 29 Minimal Residual Disease
-Day 29 M2
- or MRD ≥ 1% day 29
- <10yr, WBC <50K
– RER, no CNS dz
- MRD < 0.1% day 29
New Drug for TNew Drug for T--cell ALLcell ALL
HD MTX +/-Nelarabine
IV MTXIV MTX
HD MTX
CD
Lymphoblast
Lineage Specific Antigens
Drug
Transporters
Cytokine
Receptors
Signal Transduction
Pathways
Transcription/Translation
Immunotherapy
Targeted Leukemia Targeted Leukemia TherapyTherapy
Arceci & Cripe, Ped Clin NA (49) Dec. 2002
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Ruxolitinib
MK-2206
Cixutumumab
Erlotinib
Bortezomib
Obatoclax
Bevacizumab, Cediranib, Pazopanib
Crizotinib
Sorafenib
Vismodegib
SirolimusTemsirolimus RO4929097
The The first molecularly targeted drugfirst molecularly targeted drug
Faderl S et al. Oncology (Huntingt).
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bcr
abl
bcr-
abl
9 9+
Fusion Protein with Tyrosine Kinase Activity
22-
Upregulate DNA, Proliferation
LLS funded research
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Targeted Therapy: Targeted Therapy: the way of the futurethe way of the future
Adding a single drug, Imatinib, to chemotherapy increased survival from 30% to 70%
Adding New Agents into Adding New Agents into Therapy: AALL07P1Therapy: AALL07P1
T. Horton Study Chair
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Day Day 1 2 3 4 51 2 3 4 5 8 9 108 9 10 1111 15 16 17 18 22 3615 16 17 18 22 36
PEG
BM
VCR
VCR VCR
Dex
Mitox
ADVL1114: TemsirolimusADVL1114: Temsirolimus
PEGVCR
Dex
IT MTX/ITT
Tem Tem Tem
IT MTX CNS 3 only
LLS funded research
Monoclonal Antibodies: Monoclonal Antibodies: Targeting specific cancer proteinsTargeting specific cancer proteins
Agent Mechanism of Action Target
Rituximab antibody to CD-20 B-ALL
Epratuzamab antibody to CD-22 B-ALL
Alemtuzumab antibody to CD-52 B & T-ALL
Combotox antibody to CD-19 & 22 B-ALL
BlinatumomabAttach patient CD3 T-cells to CD19 B-ALL
Moxetumomab antibody to CD-22 B-ALL
Inotuzumab antibody to CD-22 B-ALL
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Mode of Action of Mode of Action of BiTEBiTE®® Antibody Antibody BlinatumomabBlinatumomab
�� BlinatumomabBlinatumomab (MT103) is a (MT103) is a BispecificBispecific TT--cell Engager cell Engager ((BiTEBiTE) antibody designed to direct ) antibody designed to direct cytotoxiccytotoxic TT--cells to cells to CD19 expressing cancer cellsCD19 expressing cancer cells
Bargou R., et al. Science 2008;321(5891):974-977.
αααα-CD19
Antibody
αααα-CD3
Antibody
VL
VH
VL
Target AntigenCD19
CD3
RedirectedLysis
T Cell
Tumor
Cell
Blinatumomab
BiTE®
VH
Adult phase 1 Blinatumomab Trial: Adult phase 1 Blinatumomab Trial: Best Response During First 2 CyclesBest Response During First 2 Cycles
Cohort 1
15 µg/m²/d
(n = 7)
Cohort 2a
5-15 µg/m²/d
(n = 5)
Overall
(N = 12)
CR/CRh*, n (%)
CR
CRh*
Non-responder
Not available
5 (71)
2 (29)
3 (43)
1 (14)
1 (14)
4 (80)
4 (80)
0
1 (20)
0
9 (75)
6 (50)
3 (25)
2 (17)
1 (8)
MRD response (<10-4), n (%)
MRD response
No response or progression
Not available
5 (71)
1 (14)
1 (14)
4 (80)
1 (20)
0
9 (75)
2 (17)
1 (8)
CRh*: CR with only partial hematologic recovery: ≤ 5% blasts in the bone marrow, no evidence of circulating blasts or extramedullar disease, partial recovery of peripheral blood counts.
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What is CARTWhat is CART--19 (CTL019) Immunotherapy?19 (CTL019) Immunotherapy?
Custom-designed T cells engineered to seek out the CD 19 + B-ALL cells in the body. These
specialized T cells can target the B cell leukemia, attach to its CD19 protein and then kill off the
leukemia cell.
T cells are workhorses of the immune system. They recognize cells that don’t belong and attack them. However, T cells are blind to cancer cells,
which fly under the radar.
Immunotherapy reprograms a patient’s own immune system to better fight cancer.
LLS funded research
Clinical Update of Pediatric and Adult ALL
Patients treated with CART19
5 Children -Refractory or 3rd+ Relapse-3 to 8+ prior therapies-4 with prior all BMT
• 4 CR, 3 A&W up to 1 year out•1 relapsed with CD 19 (-) leukemiaNow Infusing 2-3/month (over 16 total)
•1 Adult•1 CR
Barrett, D et al. AACR 2013
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Take Home MessageTake Home Message
1) We are curing more and more children with ALL
2) Conventional chemotherapy is not going to make much more of a difference
3) Targeted therapy is much more specific and often less toxic
4) Todays experimental therapy (Phase 1) is tomorrows cure
5) Adolescents and Young adults should be treated like Children (when it comes to ALL)
Side Effects of Side Effects of TherapyTherapy
Cara L. Simon, Ph.D.Cara L. Simon, Ph.D.
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Side Effects of TreatmentSide Effects of Treatment
�� Can occur after chemotherapy, Can occur after chemotherapy, radiation therapy, or supportive care radiation therapy, or supportive care therapytherapy
�� Type of cancer, its location and age of Type of cancer, its location and age of the child will affect the severity of the the child will affect the severity of the side effectsside effects
�� Side effects can encompass all body Side effects can encompass all body symptomssymptoms
�� Curesearch.orgCuresearch.org is a is a also a great pediatric also a great pediatric reference reference for parents and families newly for parents and families newly diagnosed, in treatment, at the end of diagnosed, in treatment, at the end of treatment and after treatment and after treatmenttreatment
LLS has top notch resources
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Most common side effects Most common side effects of ALL treatmentof ALL treatment
–– Hair lossHair loss
–– Bone marrow suppressionBone marrow suppression
–– Impairment of the immune systemImpairment of the immune system
–– Central nervous system complicationsCentral nervous system complications
–– Musculoskeletal complicationsMusculoskeletal complications
–– Gastrointestinal complicationsGastrointestinal complications
–– Growth and developmentGrowth and development
–– PainPain
Hair LossHair Loss
–– Also Also called alopeciacalled alopecia
–– Some chemotherapy causes loss Some chemotherapy causes loss or thinning of hairor thinning of hair
–– Typically starts 14 days after Typically starts 14 days after treatment is startedtreatment is started
–– Hair grows back when treatment Hair grows back when treatment is finished or treatment becomes is finished or treatment becomes less intensiveless intensive
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Side Effects of TreatmentSide Effects of Treatment
�� Bone marrow suppressionBone marrow suppression
–– Most Most common dosecommon dose--limiting component of limiting component of cancer therapycancer therapy
–– Bone marrow provides environment for Bone marrow provides environment for formation of red blood cells, white blood formation of red blood cells, white blood cells and plateletscells and platelets
Bone marrow suppressionBone marrow suppression
AnemiaAnemia
��Also means low red blood cell countAlso means low red blood cell count
��Red blood cells carry oxygen Red blood cells carry oxygen throughout the bodythroughout the body
��May May cause shortness of breath, cause shortness of breath, headache, feeling tired, fast heart rate, headache, feeling tired, fast heart rate, pale pale skinskin
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Bone marrow suppressionBone marrow suppression
ThrombocytopeniaThrombocytopenia
��Also means low platelet countAlso means low platelet count
��Platelets stop bleeding by forming clotsPlatelets stop bleeding by forming clots
��Risk of bleeding when platelet count is Risk of bleeding when platelet count is lowlow
��Signs of low platelets: bruising or Signs of low platelets: bruising or petechiaepetechiae, bleeding, black stools, bleeding, black stools
Bone Marrow SuppressionBone Marrow Suppression
NeutropeniaNeutropenia
��Reduction in circulating neutrophilsReduction in circulating neutrophils
��Absolute Neutrophil Count (ANC)Absolute Neutrophil Count (ANC)
��Severity can be mild, moderate or Severity can be mild, moderate or severesevere
��Can be asymptomatic, fevers can Can be asymptomatic, fevers can occuroccur
��Increases risk for serious infection, risk Increases risk for serious infection, risk increases with prolonged neutropeniaincreases with prolonged neutropenia
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Side Effects of TreatmentSide Effects of Treatment
�� Impairment of the immune systemImpairment of the immune system
–– Increased risk for infectionIncreased risk for infection
–– PCP PCP prophylaxisprophylaxis-- bactrimbactrim, , pentamidinepentamidine, , atovaquoneatovaquone
–– Routine immunizations are held during Routine immunizations are held during treatment and for a time after therapy treatment and for a time after therapy has ended has ended
–– Yearly Flu vaccine recommendedYearly Flu vaccine recommended
Central Nervous SystemCentral Nervous System
�� Central nervous system complicationsCentral nervous system complications
–– Cognitive deficitsCognitive deficits
–– Behavioral changesBehavioral changes
–– Neuropathic pain, Flat Footed GaitNeuropathic pain, Flat Footed Gait
�� RareRare
–– SeizureSeizure
–– StrokeStroke
–– Change in Mental StatusChange in Mental Status
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Musculoskeletal ConcernsMusculoskeletal Concerns
�� Steroid Steroid MyopathyMyopathy
�� WeaknessWeakness
�� OsteonecrosisOsteonecrosis
�� OsteopeniaOsteopenia
�� Increased risk of Bone FracturesIncreased risk of Bone Fractures
�� Pain at bone marrow sitesPain at bone marrow sites
Gastrointestinal Gastrointestinal
––MucositisMucositis
––Nausea/vomitingNausea/vomiting
––Diarrhea/constipationDiarrhea/constipation
––Perirectal cellulitisPerirectal cellulitis
––Chemical or reactive hepatitisChemical or reactive hepatitis
––PancreatitisPancreatitis
––VenoVeno--occulsiveocculsive diseasedisease
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Side Effects of TreatmentSide Effects of Treatment
�� Growth and developmentGrowth and development–– Monitor throughout treatmentMonitor throughout treatment
–– Intervene earlyIntervene early
�� PainPain–– Can be acute and/or chronicCan be acute and/or chronic
–– May be from disease and/or treatmentMay be from disease and/or treatment
–– Treat underlying cause of pain Treat underlying cause of pain
–– Pharmacologic and nonPharmacologic and non--pharmacologic pharmacologic treatment of paintreatment of pain
Psychosocial EffectsPsychosocial Effects
�� FearFear
–– Fear of unknownFear of unknown
–– Treatment and proceduresTreatment and procedures
�� Guilt Guilt
–– Parents often feel guilty for not knowing that Parents often feel guilty for not knowing that their child was sicktheir child was sick
–– Siblings may feel guilty that they are healthySiblings may feel guilty that they are healthy
–– Something they did caused thisSomething they did caused this
LLS Care for the Caregivers
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Psychosocial EffectsPsychosocial Effects
�� AngerAnger
–– Feeling angry is a normal reactionFeeling angry is a normal reaction
–– Steroid behaviorSteroid behavior
�� DepressionDepression
–– Feeling sad or blue is normal reaction to Feeling sad or blue is normal reaction to diagnosis and treatmentdiagnosis and treatment
–– The changes in family routine may bring The changes in family routine may bring feelings of social isolation and loss feelings of social isolation and loss
No Stigma for seeking therapy/support
Quality of life (QOL)Quality of life (QOL)
�� Numerous studies on treatment of ALL Numerous studies on treatment of ALL and QOL and QOL
–– QOL impaired during treatmentQOL impaired during treatment
–– QOL can be affected both on therapy and QOL can be affected both on therapy and after therapyafter therapy
–– Children/adolescents with ALL have Children/adolescents with ALL have decreased QOL when compared to normsdecreased QOL when compared to norms
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SurvivorshipSurvivorship
�� Patients should be followed annually, Patients should be followed annually, even when years off therapyeven when years off therapy
�� Late effects need to be screened Late effects need to be screened
–– CardiovascularCardiovascular
–– Growth/ DevelopmentGrowth/ Development
–– School PerformanceSchool Performance
–– Liver and renal functionLiver and renal function
–– Radiation field second cancer screenRadiation field second cancer screen
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